Using a set of surface markers including IgD and CD38, human tonsillar B cells were classified into the following discrete subpopulations: 1) naive B cells, 2) germinal center cells which undergo proliferation, apoptosis, somatic mutation, isotype switching, as well as differentiation into either memory or plasma cells, and 3) memory B cells. In an attempt to characterize B cell molecules relevant to the germinal center reaction, RNA subtraction experiments were performed using highly pure naive B cells and germinal center B cells. These experiments resulted in the identification of a number of novel cDNA fragments, four of which have been selected based on preliminary data regarding their pattern of expression and structural characteristics. Accordingly, it is our hypothesis that the products of these genes may be involved in the control of specific and/or critical germinal center B cell functions, such as Ig gene somatic mutation, isotype switching or differentiation. The specific aims of this project are: 1) To complete the characterization of four novel human genes expressed by B cells undergoing germinal center reaction. 2) To study the regulation of germinal center B cell specific molecules in culture systems recapitulating the process of B cell immunopoiesis. 3) To identify the biological functions of the products of these germinal center specific genes. These studies will help characterizing novel molecules that may represent key elements within the machinery controlling among others, processes Ig gene somatic mutation and isotype switching. Additionally, the pattern of expression of the newly identified genes will be assessed within germinal center derived B cell malignancies. These studies may help reaching a better understanding of the connections between the processes of normal B cell differentiation and the development of germinal center malignancies.